Abstract
Polycyclic aromatic hydrocarbons (PAHs)/aryl hydrocarbon receptor (AhR) regulate the expression of target genes, including drug transporter genes which harbor xenobiotic response element (XRE) in their promoter regions. Thus, PAHs/AhR could alter the toxicokinetic profile of many nephrotoxic drugs, including aminoglycosides. In the current study, we investigated the expression and localization of AhR and megalin in rat kidney. Furthermore, we investigated whether AhR and its ligands could modulate the expression of megalin and consequently the gentamicin-induced nephrotoxicity (GN) in rats. Both megalin and AhR receptors are expressed in the proximal tubules of the rat kidney. Treatment with AhR agonist benzo(a)pyrene aggravated GN as indicated by a significant increase in serum creatinine, BUN, KIM1, NAGL, CD-86, and urinary albumin/creatinine ratio. On the other hand, treatment with AhR antagonist resveratrol ameliorated GN as manifested by a pronounced decrease in the aforementioned parameters. The effects of AhR ligands on GN were associated with altered expression of megalin receptor.
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Abbreviations
- AhR:
-
Aryl hydrocarbon receptor
- PAHs:
-
Polycyclic aromatic hydrocarbons
- XRE:
-
Xenobiotic response element
- GN:
-
Gentamicin-induced nephrotoxicity
- BaP:
-
Benzo(a)pyrene
- PTCs:
-
Proximal tubule cells
- Rv:
-
Resveratrol
- SC:
-
Subcutaneous
- IP:
-
Intraperitoneal
- h:
-
Hour
- min:
-
Minutes
- KIM1:
-
Kidney injury molecule 1
- NGAL:
-
Neutrophil gelatinase-associated lipocalin
- DMSO:
-
Dimethyl sulfoxide
- BUN:
-
Blood urea nitrogen
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Acknowledgments
The authors would like to thank Professor Ahmed M. Ibrahim Mansour, Professor of Pharmacology and Toxicology, Faculty of Pharmacy (Boys), Al-Azhar University, for facilitating the work; great gratitude to boards of directors of EPICO Pharmaceuticals Company for their kind help and support; and deepest thanks to Dr. Sayed Abdel Raheem, Ass-Professor of Histopathology, Faculty of Medicine, Al-Azhar University, Cairo.
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Mokhtar, M.M., Khidr, E.G., Shaban, H.M. et al. The effect of aryl hydrocarbon receptor ligands on gentamicin-induced nephrotoxicity in rats. Environ Sci Pollut Res 27, 16189–16202 (2020). https://doi.org/10.1007/s11356-020-08073-z
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DOI: https://doi.org/10.1007/s11356-020-08073-z